TCD with Transfusions Changing to Hydroxyurea - SDMC

描述（由申请人提供）： 中风发生在5-10%的SCA儿童中，并且是导致严重运动和神经认知缺陷的破坏性临床事件。为了帮助预防初始（原发性）卒中，年轻SCA患者可以接受定期TCD筛查，以识别脑血管系统中动脉流速升高的儿童，这预示着原发性卒中风险增加。对于大脑中动脉（MCA）或颈内动脉（伊卡）的时间平均最大流速（TAMV）升高至“异常”范围（= 200 cm/sec）的儿童，长期红细胞输注可显著降低原发性卒中的风险。在这种情况下，输血可以预防首次中风，但有严重的副作用，限制其长期效用。输血传播感染因子，导致红细胞同种抗体或自身抗体形成，并导致铁过载。输血获得性铁过载被认为是年轻SCA患者接受输血预防原发性卒中的发病率和死亡率的来源。螯合疗法可以帮助防止铁的积累，但难以耐受，不遵守是常见的。显然需要一种替代预防性输血的方法来预防卒中，特别是一种还提供了解决输血获得性铁过载问题的机会的方法。我们提出了一个III期随机临床试验的儿童镰状细胞贫血（SCA）和异常经颅多普勒（TCD）速度，被称为“TCD与输液改为羟基脲”（TWiTCH）试验。我们的假设是，羟基脲可以维持与红细胞输注相似的TCD速度，因此可以作为非劣效治疗，用于SCA高危儿童的一级卒中预防。TWiTCH试验的主要目的是比较标准治疗（输血）与替代治疗（羟基脲）在维持因TCD速度异常而长期输血的SCA儿童的TCD速度方面的效果。TWiTCH的其他目的包括比较标准治疗与替代治疗的原发性卒中发生率、确定非卒中神经系统事件和其他镰状细胞相关事件的频率、管理铁过载、评估生长和发育、记录不良事件和测量生活质量。(End摘要）

DESCRIPTION (provided by applicant): Stroke occurs in 5-10% of children with SCA, and is a devastating clinical event that results in severe motor and neurocognitive deficits. To help prevent an initial (primary) stroke, young patients with SCA can receive periodic TCD screening to identify children with elevated arterial velocities in the cerebral vasculature, which portends increased primary stroke risk. For children with time-averaged maximum velocities (TAMV) in the middle cerebral artery (MCA) or internal carotid artery (ICA) elevated to the "abnormal" range (=200cm/sec), chronic erythrocyte transfusions significantly lower the risk of primary stroke. In this setting, transfusions can prevent first stroke but have serious side-effects limiting their long-term utility. Transfusions transmit infectious agents, lead to erythrocyte alloantibody or autoantibody formation, and result in iron overload. Transfusion acquired iron overload is recognized as a source of morbidity and mortality for young patients with SCA receiving transfusions for prevention of primary stroke. Chelation therapy can help prevent iron accumulation, but is difficult to tolerate and non-compliance is common. An alternative to transfusion prophylaxis for primary stroke prevention is clearly needed, especially one that also provides an opportunity to address the issue of transfusion acquired iron overload. We propose a Phase III randomized clinical trial for children with sickle cell anemia (SCA) and abnormal Transcranial Doppler (TCD) velocities, termed the "TCD With Transfusions Changing to Hydroxyurea" (TWiTCH) trial. Our hypothesis is that hydroxyurea can maintain a similar TCD velocity as erythrocyte transfusions, and therefore serve as non-inferior therapy, for primary stroke prevention in high risk children with SCA. The primary aim of the TWiTCH trial is to compare standard therapy (transfusions) to alternative therapy (hydroxyurea) for maintenance of TCD velocities in children with SCA on chronic transfusions for abnormal TCD velocities. Additional aims of TWiTCH include comparison of standard to alternative therapy for incidence of primary stroke, determination of the frequency of non-stroke neurological events and other sickle cell-related events, management of iron overload, assessment of growth and development, recording of adverse events, and measurement of quality of life. (End of Abstract)